This program project grant is concerned with the exploration of new approaches leading to the development of more effective cancer therapy through the integrated and yet diversified contributions of various laboratories of the Grace Cancer Drug Center (GCDC) at Roswell Park. New compounds, synthesized within this program or obtained from outside sources, are being tested for biological activity in mammalian cell systems in vitro and in tumor bearing rodents. New tumor models are being developed to improve the identification of new compounds with potential clinical value. New types of drug administration are being explored. The preclinical toxicology and pharmacology of compounds of interest is being studied in several animal species prior to their initial clinical trial. Studies of the biochemical and pharmacological basis for selective cellular effects of drugs are being carried out in relation to the drug development activities in a variety of experimental systems and provide an important source of information leading to the design of additional drugs and combination treatments with improved selectivity of action. These studies include investigations on cell membrane function or interactions of drugs and hormones with chromatin, on drug biotransformation and disposition, on the basis for drug toxicity to tumor and normal cells including the modification of toxicity through metabolic modulation and through modification of regimens and treatment modalities. The development of new anticancer drugs and new forms of treatment is integrated closely with both basic progress in the biochemical pharmacology of anticancer drugs and fundamental studies on the regulation of cell metabolism carried out with other grant support in the GCDC: interactions among these approaches and sources of support provide an optimal background for the formulation of new ideas and implementation of studies leading to advances in the therapy of cancer.